Bone remodeling, a process responsible for the continuous renewal of the adult human skeleton, is carried out by osteoclasts and osteoblasts, two specialized cell types that originate from hematopoietic and mesenchymal progenitors of the bone marrow, respectively. A continuous and orderly supply of these cells is essential for skeletal homeostasis, as increased or decreased production of osteoclasts or osteoblasts and/or changes in the rate of their apoptosis are largely responsible for the imbalance between bone resorption and formation that underlies several systemic or localized bone diseases.
Enhanced osteoclast activity plays a major role in the pathogenesis of postmenopausal osteoporosis, Paget's disease, lytic bone metastases, multiple myeloma, hyperparathyroidism, rheumatoid arthritis, periodontitis, and hypercalcemia of malignancy. These clinical problems are associated with significant morbidity or mortality, and affect more than 10 million patients in the United States. However, only a limited number of agents that inhibit osteoclast formation or bone resorption are available and for most their mechanisms of action are unknown. Furthermore, many of these agents have significant side effects that limit their utility. Thus, there exists a need for the identification and characterization of inhibitors of osteoclast formation and bone resorption as part of the continuing search to provide therapeutic benefits for these patients.
Conversely, decreased osteoclast activity plays a major role in the pathogenesis of osteopetrosis, Albright's osteodystrophy, and achondroplasia, for which there is no specific therapy. Thus, there also exists a need for the identification and characterization of treatments that enhance osteoclast formation and bone resorption in order to provide successful therapies for these patients.
Identification of the mechanisms involved in bone disorders is crucial for the understanding of bone physiology. While numerous genes and gene families (and the polypeptides encoded by them) that participate in the regulation of bone cells have been identified and cloned, their functions have not been clearly delineated due to the complexities of the bone formation pathways. A great need exists for the definitive identification of targets for the treatment of bone disorders, including bone resorption disorders such as postmenopausal osteoporosis, Paget's disease, lytic bone metastases, multiple myeloma, rheumatoid arthritis, hypercalcemia of malignancy, osteopetrosis, Albright's osteodystrophy, and achondroplasia.